This invention relates to the field of pathologies of the oral cavity caused by fungi.
One of the most common and stubborn infections of the mouth and throat is Candidiasis. Thrush or acute candidiasis is caused by extensive candidal invasion of the oral mucosal epithelium. Thrush presents as creamy, yellow tufts which can be readily wiped off with a swab to expose a red and inflamed area of epithelium. The cottony tufts are the result of extensive infiltration of candidal hyphae into the mucosal epithelium.
Although thrush is most common in infants, it also occurs in adults that are immunocompromised, undergoing broad spectrum antibiotic treatment, undergoing corticosteroid treatment, diabetics and anemics. In adult patients, particularly immunosuppresed patients, thrush is treated with large amounts of azole compounds such as miconazole, itraconazole, econazole, ketoconazole or fluconazole. Among thrush patients not already undergoing broad-spectrum antibiotic treatment, broad-spectrum antibiotics are frequently prescribed in combination with fungicide therapy to avoid or treat any secondary bacterial infections. Infants are usually treated with fungicidal suspensions if the infection does not spontaneously clear.
Chronic candidiasis is both far more common and far more difficult to treat than thrush. Candidiasis is characterized by less extensive innervation of the epithelium by the Candidal hyphae than thrush.
Candidal proliferation on denture surfaces is a common, chronic, but minor form of candidiasis. Inflammation of the epithelium under dentures, denture stomatitis, may be caused by the proliferation of C. albicans in the interface between the denture-bearing mucous membrane and the denture surface. The lower denture-bearing area is typically freely exposed to saliva, and consequently denture stomatitis is rarely seen in this site. However, a close-fitting upper denture creates a microenvironment cut-off from any protective effects of saliva. When C. albicans proliferates under a denture, it is held in prolonged contact with the mucous membrane and presumably acts as an irritant.
Denture stomatitis is considered a common cause of inflammation of the epithelium near the corners of the mouth, angular stomatitis, among ambulatory patients. Typical treatment requires vigorous use of topical oral nystatin or amphotericin B to resolve denture stomatitis and associated angular stomatitis. During treatment, the dentures must be worn as little as possible to allow the drug to the reach affected area, thus, inconveniencing suffering denture wearers.
Candidal leukoplakia is a less common type of chronic candidiasis, appearing as a thick keratizined lesion on or about the tongue. Microscopically, a candidal leukoplia plaque consists of a thick layer parakeratinized epithelium invaded by candidal hyphae. These keratinized plaques of chronic candidiasis are tough, adherent, and often irregular in thickness, persistent, and therefore, unlike the soft friable plaques of thrush. Common sites are the commissures of the tongue and cheeks. Treatment of candidal leuloplakia infections are difficult since the intracellular growth of the candida makes it less accessible to antifungal drugs. Absent treatment, these leukoplakias often cover large areas of the mouth and tongue, making eating painful and causing significant social anxiety among the afflicted.
A number of rare forms of chronic mucocutaneous candidiasis appear associated with various immune disorders. Familial chronic mucocutaneous candiasis is a rare, recessive, immune disorder which confers a tendency to develop chronic, leukoplakia-like plaques. Diffuse chronic mucocutaneous candidiasis is associated with susceptibility to bacterial infections, particularly of the respiratory tract, and other fungal infections. Its lesions may extend down the pharynx or larynx and when affecting the mouth and lips, can be severely disfiguring. Candida endocrinopathy syndrome appears to be transmitted as an autosomal recessive gene. The candidal infections tend to be mild and dermal lesions are rare. The main features are the associated endocrine deficiencies. Most common is hypoparathyroidism, but hypoadrenalism and almost any other type of endocrine deficiency can develop.
Treatment for all these candidal immune disorders are difficult. If the immunological defect can be identified, as is sometimes the case with diffuse chronic mucocutaneous candidiasis, treatment may be possible, but generally treatments are ineffective because they fail to address the underlying immunological disorder that allows the candida to flourish.
The foregoing discussion indicates that an effective fungicide against a wide range of candidal pathologies useful in immuno-compromised patients, children, and the elderly that can either be topically applied or systemically applied to treat the chronic candidal infections like candidal leukoplakia that is resistant to topical treatment would be a significant advance to the art. Such a fungicidal should preferably have low toxicity and even more preferably possess anti-inflammatory properties. Lastly, the fungicidal should also have minimal cross reactivity with other drugs so that it may be simultaneously prescribed with the complicated treatment regimens of the elderly and chronically ill-two groups likely to suffer candidiasis.
The invention includes a composition and method of treatment of fungal pathologies of the oral cavity or fungal growth on the surface of dentures. In a preferred embodiment of the invention a therapeutically effective amount of one or more peptides selected from the group of peptides with a C-terminal sequence consisting of KPV (SEQ ID NO: 1), HFRWGKPV (SEQ ID NO: 3), and SYSMEHFRWGKPV (SEQ ID NO: 4) used in combination with a therapeutically effective amount of a fungicide selected from the group consisting of: itraconazole, econazole, ketoconazole, miconazole and fluconazole and dissolved into a carrier. More preferably still each peptide has the primary sequence of KPV (SEQ ID NO: 1) or VPK-Ac-CC-Ac-KPV (SEQ ID NO: 8)(Ac=Acetyl group). Pharmacologically effective concentrations may be as low as 10xe2x88x9212 M but may be as high 10xe2x88x924 M. Pharmacologically effective concentration of these peptides may be incorporated into commercial formulations of creams, gels, mouthwashes, toothpastes, tablets, or atomized sprays.
In another preferred embodiment of the invention these peptides are topically or systemically applied to treat a candida infection of the oral cavity. In yet another embodiment of the invention these peptides are used in combination with a therapeutically effective amount of a gram positive or gram negative antibiotic to prevent or treat secondary bacterial infections of the oral cavity or on the surface of dentures.